Osteoarthritis (OA) is a degenerative and inflammatory condition in which there is a loss of cartilage matrix. It is a particularly prevalent cause of lameness and an expensive equine health problem. It is also a common disease of dogs. Clinically, animals with OA present with stiffness or lameness. Lameness is because of a combination of joint pain and restricted movement of the joint. There are many medical therapeutic options. Corticosteroid, polysulfated glycosaminoglycans, or hyaluronic acid injections are frequently used in horses. In both small animals and horses, nonsteroidal anti-inflammatory drugs are the basic treatment and are most commonly administered PO.[4-6]
Products called “nutraceuticals” have recently appeared on the market. The term “nutraceutical” was coined from “nutrition” and “pharmaceutical” in 1989 and was defined as “a food (or part of a food) that provides medical or health benefits, including the prevention and/or treatment of a disease.” However, the term nutraceutical as commonly used in marketing has no regulatory definition. Under the Dietary Supplement Health and Education Act of 1994 (DSHEA), the term “dietary supplement” is defined as a product taken by mouth that contains a “dietary ingredient” intended to supplement the diet. The “dietary ingredients” in these products can include vitamins, minerals, herbs or other botanicals, amino acids, and substances such as enzymes, organ tissues, and metabolites. Dietary supplements can also be extracts or concentrates, and can be found in many forms such as tablets, capsules, softgels, gelcaps, liquids, or powders. These different definitions concern human consumers and not pets. According to the North American Veterinary Nutraceutical Council (NAVNC), a nutraceutical is “a substance produced in purified or extracted form which, when administered orally to patients, aims to provide them the necessary elements for their structure and normal function to better their health and well-being,” but this definition has no regulatory meaning. In Europe, no specific indications can be legally recognized for nutraceuticals as no official evidence of efficacy is required to market them and manufacturers do not have to conduct the extensive studies that are necessary to obtain official approval for marketing medicinal products like antibiotics or anti-inflammatories.
The veterinary profession has ethical obligations to ensure effective and safe service and to base therapeutic decisions on scientific evidence.[12-14] Because OA has important clinical consequences on animals, it is important to know the efficacy of products, such as nutraceuticals, that are used in veterinary medicine.
Although evidence-based medicine (EBM) might logically help veterinarians make more informed decisions, obstacles to its widespread adoption have been reported, including the lack of high quality patient-centered research,[15-18] and the inadequacy of EBM tools to the busy daily practice because of the limited time available to veterinarians to keep up to date with the large quantity of scientific literature.[14, 19] Other authors have suggested that, as in human medicine, information such as systematic reviews should be available so that practitioners devote their scarce reading time to selected quality scientific information. Systematic reviews are still not common in veterinary medicine. In human medicine, their reporting has been standardized.
The objectives of this study were to review the literature about the usefulness of nutraceuticals for improving clinical signs of pain or abnormal locomotion in horses, dogs, and cats with OA, to illustrate the issue of lack of scientific information about this topic, and to suggest a general methodology of conducting and reporting a systematic review that would improve transparency both for scientists and veterinary practitioners.
- Top of page
- Material and Methods
- Supporting Information
Through our searches, we were able to identify a total of 67 eligible studies; however, only 22 studies fulfilled the criteria.[4, 27-47] Forty-five studies were not selected for several reasons that are detailed in Figure 1. Two of the 22 studies were performed in a horse model of OA.[30, 31] The key properties of studies are reported in Table 2. The detailed results of quality assessment (step 1) can be accessed online (Addendum), whereas the total scores of quality (step 1) and the results of steps 2–5 are reported in Table 3.
Table 2. Key features of selected studies. Each study has an ID (identity) number and its publication is referenced (Ref).
|1||||Horse||UC-II GLU and CS||NRCT, PBO, NOA||25||150||SOA||Y|
|2||||Horse||Compound (MA, GLU, MSM, AOV)||RCT, DB, PBO, NOA||40||28||SOA||Y|
|3||||Horse||ASU||RCT, DB, PBO, MOA||16||70||SOA||Y|
|4||||Horse||Low molecular weight CS Native CS||RCT, DB, PBO, MOA||10||70||SOA||N|
|5||||Horse||AOV||RCT, DB, PBO,NOA||8||14||OA||Y|
|6||||Dog||βG||RCT, DB, PBO, NOA||46||56||SUA||N|
|7||||Dog||GH||RCT, DB, PBO, NOA||60||56||SUA||N|
|8||||Dog||O3FA||RCT, DB, NOA||177||90||SOA, SUA||Y|
|9||||Dog||O3FA||RCT, DB, NOA||131||90||SOA, SUA||N|
|10||||Dog||O3FA||RCT, DB, NOA||127||180||SUA||N|
|11||||Dog||O3FA||RCT, DB, NOA||38||90||SOA, SUA, OA||N|
|12||||Dog||UC-II HCA Combinations with CM||RCT, DB, PBO, NOA||25||120||SUA||Y|
|13||||Dog||Compound (GLU, CS)||RCT, DB, PBO, NOA||35||70||SOA||Y|
|14||||Dog||GLMP||RCT, DB, PBO, NOA||81||56||SOA, SUA||Y|
|15||||Dog||GLMP||RCT, DB, NOA||96||42||SOA||Y|
|16||||Dog||GLMP||RCT, DB, NOA||31||42||SOA||Y|
|17||||Dog||GLMP CS||RCT, DB, PBO, NOA||58||84||SOA, SUA||N|
|18||||Dog||Compound (GLU, CS, MN)||RCT, DB, PBO, NOA||71||60||SOA, SUA, OA||Y|
|19||||Dog||UC-II||RCT, DB, PBO, NOA||15||90||SUA||Y|
|20||||Dog||SPMC||RCT, DB, PBO, NOA||35||56||SOA, SUA||Y|
|21||||Dog||P54FP||RCT, DB, PBO, NOA||54||56||SOA, SUA, OA||Y|
|22||||Cat||Compound (O3FA, GLMP, GLU, CS)||RCT, DB, NOA||40||70||SOA, SUA, OA||Y|Table 3. Summary of steps 1–5.
In horses, soybean and avocado unsaponifiables (ASU) extracts had no effect. and global strength of evidence of efficacy was low for non-denatured type II collagen (UC-II); CS; combinations of oligo-elements, amino acids, and vitamins (AOV); and combinations of myristoleic acid (MA), GLU, methylsulfonylmethane (MSM), hydrolyzed collagen (HC), and AOV.
In dogs, hydroxycitric acid (HCA) and extract of Indian and Javanese turmeric (P54FP) were not effective, although for the latter veterinarians reported an improvement in clinical signs in contradiction with objective data that were obtained with a force plate. Global strength of evidence of efficacy was low in studies demonstrating a significant effect for the use of β-1,3/1,6 glucans (β G); gelatine hydrolysate (GH); UC-II alone or combined with HCA or with chromium nacinate (CMN); special milk protein concentrate (SMPC). Two different compounds containing GLU and CS showed contradictory results: one compound had beneficial effects, although the other one (combined with manganese [MN]) had no effect. The highest global strength of evidence of efficacy was demonstrated by O3FA supplemented diets.[35-38] Green lipped mussel powder (GLMP) had a significant effect in 3 of 4 studies,[41-44] and because of this inconsistency between studies, we could not conclude to a strong indication for its clinical use.
In cats, it was not possible to recommend the use of diets supplemented with O3FA, GLMP, GLU, and CS, as only 1 study, though of high quality, had been performed for this product.
This review identified several major methodological issues in clinical trials: the limited numbers of rigorous randomized controlled trials and of patients in studies, the lack of objective outcome measures, the uncommon use of the concept of “effect size,” the risk of conflict of interest, the lack of standardization of dosages and duration of treatments.
- Top of page
- Material and Methods
- Supporting Information
In this review, it is the potential of nutraceuticals to alleviate the clinical signs of OA that was evaluated, rather than any potential disease (structure)-modifying effects. Only clinical and in vivo experimental studies were selected. This does not mean that we considered in vitro studies as being of low quality. Their conclusions are simply less easy to generalize to the population of animals and are less useful to answer clinical questions referring to improvement of signs of pain and abnormal locomotion.
We found 4 randomized controlled trials in dogs concerning diets supplemented with O3FA, which were of high quality and demonstrated a significant effect on clinical signs of OA.[35-38] A meta-analysis in humans found that dietary supplementation with fish oil, which is enriched in O3FA, especially eicosopentanoic acid (EPA) and docosahexaenoic acid (DHA), provides benefits in rheumatoid arthritis. O3FA may lower arachidonic acid concentrations and alter the production of eicosanoids to less inflammatory forms. In addition, O3FA would reduce the expression of cartilage degrading enzymes, cyclooxygenase-2, and inflammation-inducible cytokines.
Although, in dogs, no effect with GLMP-enriched diet was reported, 3 other studies demonstrated a significant improvement of the outcome measures in the tested group versus the control group in this species. According to this inconsistency, we could not recommend the use of GLMP in OA. However, the reason for which no effect was observed in the 1st study might be because of the dose administered, which was only 10 mg of GLMP per day and per kg, whereas dogs received between 20 mg and 100 mg per day and per kg in the other studies.[41-43] Dosage should be standardized to compare nutraceuticals objectively. Moreover, a high quality study in cats demonstrated a beneficial effect of a diet supplemented with O3FA, GLU, and GLMP. GLMP has been shown to contain a unique O3FA, eicosatetraenoic acid (ETA), which appears to act as dual inhibitor of arachidonic acid oxygenation by both the cyclooxygenase and lipoxygenase pathways. Other controlled clinical trials should be done to establish a link between O3FA and GLMP because the effect of GLMP might be at least partly because of O3FA.
P54FP, an extract of Indian and Javanese turmeric, contains a mixture of active ingredients including curcuminoids and essential oils and has been reported to possess anti-inflammatory properties. ASU has shown, in vitro, positive effect on both the inflammatory cascade and structural components of articular cartilage matrix.[52, 53] In the identified studies, the administration of P54FP in dogs and ASU in horses resulted in no change in objective outcome measures of clinical signs of OA.[27, 30] Interestingly, results suggest that the ASU extracts can induce structural modification of the joint surface. This illustrates that nutraceuticals might be beneficial in the management of OA by reducing the progression of gross articular cartilage damage, although other methods for improving clinical signs would need to be used.
GLU and CS are nutraceuticals that are commonly used as dietary supplements in several species. There are indications that they provide prophylactic protection against synovitis, they retard the degenerative process synergistically and they modulate the metabolism of articular cartilage.According to our criteria in this review, the global strength of evidence of efficacy was low for GLU and CS. In addition, results were contradictory in the 2 studies conducted in dogs[40, 45] and, in one of 3 studies performed in horses and in the only one performed in cats, GLU and CS were part of a compound including other nutraceuticals that might have been responsible for the clinical effect as well.
Different mechanisms of action and properties have been reported for other nutraceuticals that were tested in the studies identified for this review (UC-II, β G, MA, MSM, and SPMC). The effect of AOV and HCA was evaluated without real explanation of their hypothetical mechanism of action by the investigators. In humans, UC-II reduces immune-mediated damage to joint cartilage, thereby improving joint mobility and flexibility in rheumatoid arthritis. There are indications that the amino acids in GH stimulate the synthesis of collagen in human cartilage. Feeding of β G in pigs reduces the plasma concentrations of the proinflammatory cytokines, IL-6 and TNFα and raised the concentration of the anti-inflammatory cytokine, IL-10. MA affords good protection against adjuvant-induced arthritic states in rats. The benefits of the anti-inflammatory properties of MSM in managing OA in humans has been investigated but could not be confirmed. It is speculated that SMPC contains natural factors that inhibit inflammation by suppressing neutrophil emigration from the vascular space, possibly by restricting extravasation through tight junctions. However, according to our criteria in this review, the global level of evidence of efficacy to alleviate clinical signs of OA was low for UC-II, β G, MA, MSM, SPMC, and AOV. HCA was ineffective in dogs.
This review also showed the limited numbers of rigorous randomized controlled trials and of participants in clinical studies. Among publications identified in databases, only controlled trials were considered as these constitute the highest level of evidence, which can be used for a question concerning therapeutics.[12, 13, 20] Only 22 studies were identified and, owing to this low number, the evaluation of consistency (step 4) between observations was rarely applicable. This lack of information may be because of different factors. (1) The veterinary pharmaceutical market represents only a small proportion of the pharmaceutical industry and it is unrealistic that research comparable to human medicine will be conducted in the veterinary field frequently. (2) Nutraceuticals are not considered as medicinal products. Manufacturers do not have to provide scientific information to legal authorities. They tend to conduct and publish a scientific study to justify and support the use of their product to the consumers. However, they do not necessarily have an interest in repeating such studies, as these might result in negative findings. (3) It might also be difficult for investigators to publish a study that is similar to a previous one, but that addresses some shortcomings. Peer-reviewed journals might not prioritize publication of confirmatory studies.
To evaluate the methodological quality of studies, we built a new tool consisting in a set of questions (Table 1). It was consistent with different sources of recommendations about reporting in research.[20, 25, 64-67] Some elements of those recommendations were rarely considered in the publications about nutraceuticals, such as the description of randomization, allocation concealment, sequence allocation, blinding, flux of participants, periods of recruitment and follow-up, and baseline data. On the other hand, background, objectives, interventions, statistical results, and results were usually well reported. In Table 1, the weighting of items, though obtained via a Delphi process, reflects these authors' opinions and requires criticism and further validation. It might be argued also that the CONSORT statement provides guidelines about how to report randomized controlled trials and not directly how it should be conducted. As a consequence, Table 1 would mix items that refer to the format of the manuscript (eg, how the background is adequately described in the introduction) with items that refer to the quality of the methodology (eg, how participants were blinded). However, the evaluation of the quality of the scientific information is performed via the manuscript that is available. In other words, investigators, in systematic reviews, do not often have the opportunity to check the raw data and the actual application of the methodology that is reported. Therefore, systematic reviews will remain limited to investigate published manuscripts, until a general consensus is reached by the scientific community about how to ensure transparency about data. This effort should be made at every level. For example, we suggest that our system of evaluation in this review, and the way results are reported (Table S1 in addendum), might provide transparency by providing the raw data (the references of the publications included in the review), the outcome measures (the question items), and the scores for every item, thus allowing readers to repeat the review and compare their personal rating to ours. We also suggest that Table 1 might be a useful educating tool for veterinary practitioners who are less aware of clinical epidemiology and critical review of publications. In veterinary medicine, other authors recommend developing strategies to facilitate the practice of EBM and have shown that critical reviewing helps better understand EBM concepts.
Several methodological weaknesses in the methodology of trials were identified (Table 1). First, objective outcome measures were rarely used. Lameness is traditionally evaluated semiobjectively by clinicians. Promulgators of evidence-based research recommend the use of objective instruments to validate outcomes and provide a standardized means for clinical assessment of the efficacy of veterinary treatments,[64-67] like kinematics and force plates.[27, 32, 47] We attributed a higher score to studies by means of objective outcome measures than to those relying upon semiobjective ones (eg, clinical test performed by a veterinarian) and, especially, on subjective evaluations such as owner's opinion. Secondly, the difficulty in recruiting patients and the importance of considering the power of studies and sample size in veterinary research have been emphasized. This review shows that a low number of individuals were studied. It might be argued that criteria of quality were set too high and that, for example, we could have considered a moderate level of evidence when 1 or 2 high-quality studies demonstrated a significant effect with an adequate number of individuals in each group (eg, n = 25). Innes estimated that 25 dogs per group were an adequate sample size to detect a 10% difference in peak vertical force (measured with a force-plate) between the active treatment and placebo with a power of 80%. We considered this sample size as the minimal requirement, although we are aware that power calculations vary with the expected magnitude in the difference in outcome between groups, the probability of the false-positive and false-negative conclusions one is willing to accept, and the nature of data. Quantity of valuable information was also rarely adequate according to our criteria, that is, at least 3 studies assessing the same product. Although it was adequate for O3FA and GLM, it is to note that the 4 identified studies were performed by the same team of researchers for the former,[35-38] and 2 of the 4 studies we found came from the same team for the latter.[42, 43] Thirdly, a statistically significant result does not indicate whether the observed effect has any clinical importance. The concept of “effect size,” a unitless measure of the degree to which the apparent treatment effect exceeds the placebo effect, has not been widely reported in veterinary trials. Calculation and reporting of effect size in veterinary trials is a convenient construct for comparing the magnitude of outcomes within and among trials[4, 70] and as such was considered in this review as an element of quality. Fourthly, the discussion section is difficult to evaluate and may be biased by the interests of investigators, because several studies are sponsored or supported by manufacturers. We attempted to identify objective factors of quality of discussion such as whether authors were considering trial limitations, sources of potential bias, imprecision, applicability, other relevant evidence, benefits, and harm. The assessment of publications by 2 reviewers aimed to limit subjectivity.
There were also other methodological elements that influenced the evaluation of the efficacy of nutraceuticals, such as uncontrolled composition of the marketed product and combination of the nutraceuticals with others.
It must also be noted that the duration of treatment was variable and ranged from 90 to 180 days for O3FA, whereas shorter treatments (sometimes only 2 weeks) were administered in other studies. Initial standardization is difficult as there will always be regimens (meaning dosage, treatment frequency, and treatment duration) that are not or less effective than others. Nevertheless, once a nutraceutical has been suggested to be effective in 1 group, conditions of administration should be defined if the purpose is to assess whether it is also effective in another group or to compare it with another product.
This systematic review demonstrates that the evidence of efficacy of nutraceuticals to improve pain or gait abnormalities in OA is poor, with the exception of diets supplemented with O3FA in dogs. This conclusion must be contrasted by the fact that, to date, systematic review remains an imperfect process. This article illustrates the limits of application of EBM in veterinary science with limited number of rigorous randomized controlled trials and of individuals in clinical trials. As a result of this veterinary context and the difficulty to design strong study designs, there is a risk that future systematic reviews about veterinary topics will continue to conclude that the level of evidence is not satisfactory. Although systematic reviews may also give the impression of a strong criticism by scientists on the work of their colleagues, transparency and accountability policies are widely accepted strategies to drive quality improvement and stimulate consumer choice. It is important to work on the availability of informational tools at the disposal of practitioners, such as systematic reviews. It is also essential to request more clinical studies, and less confidentiality, about medicinal products and dietary supplements that are marketed, to better inform veterinarians. The culture of only publishing truly original research has also to change before we will be able to really practice EBM. It is necessary to continue the investigation about nutraceuticals in a standardized way to evaluate their potential role as disease modifier. In addition, guidelines should be elaborated to reach a standardization of systematic review of trials and observational studies to limit heterogeneity of results and ensure fair comparisons between studies. Their reporting would be improved by internationally agreed criteria for guidelines. Before all these changes have been implemented, we will have to remain very careful in our conclusions.